This invention relates to novel nitrosourea derivatives which exhibit a high level of inhibitory activity against leukemia and tumors, to a process for the preparation thereof and to their use for pharmaceutical purposes.
There are a variety of compounds which have been proposed as being effective for inhibiting leukemia and tumors, one class of which is nitrosourea derivatives. Among the nitrosourea derivatives, streptozotocin [N-(N'-methyl-N'-nitrosocarbamoyl)-D-glucosamine] and its derivatives such as methyl glucosaminides are typical ones early developed (refer to U.S. Pat. No. 3,577,406 and U.S. Pat. No. 3,767,640, for example), but they are not satisfactory yet because of insufficient activity against leukemia and tumors and/or undesirable side effects thereof. Another class of nitrosourea derivatives is haloalkylnitrosoureas, a typical example of which is 1,3-bis(2-chloroethyl)-1-nirosourea (abbreviated as BCNU) [refer to, for example A. Goldin et al., Cancer Chemotherapy Rept., 40, 57 (1964) and T. P. Johnston et al., Journal of Medicinal Chemistry 9, 892.about.911 (1966)].
I have also investigated on the synthesis and chemical and pharmacological properties of some wide range of nitrosoureas and recently proposed, as highly interesting series of those compouns, glycosyl derivatives of nitrosoureas (refer to T. Suami et al., U.S. Pat. No. 4,086,415, U.S. Pat. No. 4,157,439 and U.S. Pat. No. 4,220,643) and hydroxy-substituted cyclohexyl derivatives of nitrosoureas (refer to T. Suami et al., U.S. Pat. No. 4,180,655). The most interesting compound of the former series is 1-(2-chloroethyl)-3-(.beta.-D-glucopyranosyl)-1-nitrosourea (abbreviated as GANU) and that of the latter series is 1-(2-chloroethyl)-3-(1,3/2N-dihydroxycyclohexyl)-1-nitrosourea (abbreviated as DONU), both of which have a broad spectrum of antitumor activity against a wide variety of experimental leukemia and tumors with positive expectation of the efficacy in human cancer chemotherapy.